title: Signal transducers and activators of transcription-3/pim1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension.
abstract: BACKGROUND
  Pulmonary artery hypertension (PAH) is a proliferative disorder associated with enhanced pulmonary artery smooth muscle cell proliferation and suppressed apoptosis. The sustainability of this phenotype required the activation of a prosurvival transcription factor like signal transducers and activators of transcription-3 (STAT3) and nuclear factor of activated T cell (NFAT). Because these factors are implicated in several physiological processes, their inhibition in PAH patients could be associated with detrimental effects. Therefore, a better understanding of the mechanism accounting for their expression/activation in PAH pulmonary artery smooth muscle cells is of great therapeutic interest.
  
  
  RESULTS
  Using multidisciplinary and translational approaches, we demonstrated that STAT3 activation in both human and experimental models of PAH accounts for the expression of both NFATc2 and the oncoprotein kinase Pim1, which trigger NFATc2 activation. Because Pim1 expression correlates with the severity of PAH in humans and is confined to the PAH pulmonary artery smooth muscle cell, Pim1 was identified as an attractive therapeutic target for PAH. Indeed, specific Pim1 inhibition in vitro decreases pulmonary artery smooth muscle cell proliferation and promotes apoptosis, all of which are sustained by NFATc2 inhibition. In vivo, tissue-specific inhibition of Pim1 by nebulized siRNA reverses monocrotaline-induced PAH in rats, whereas Pim1 knockout mice are resistant to PAH development.
  
  
  CONCLUSIONS
  We demonstrated for the first time that inhibition of the inappropriate activation of STAT3/Pim1 axis is a novel, specific, and attractive therapeutic strategy to reverse PAH.
authors.affiliation: Centre de recherche de L'Hôtel-Dieu de Québec, 10 Rue McMahon, Québec, QC G1R 2J6, Canada.
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.forename: Audrey
authors.initials: A
authors.lastname: Courboulin
authors.forename: Jolyane
authors.initials: J
authors.lastname: Meloche
authors.forename: Vincent
authors.initials: V
authors.lastname: Mainguy
authors.forename: Eric
authors.initials: E
authors.lastname: Dumas de la Roque
authors.forename: Nehmé
authors.initials: N
authors.lastname: Saksouk
authors.forename: Jacques
authors.initials: J
authors.lastname: Côté
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology*; D008928:Mitochondria / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000502:physiology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000502:physiology*; D011651:Pulmonary Artery / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000502:physiology*
chemical_list: D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1